Alkenyl-substituted spirocyclic sulfamides as inhibitors of gamma-secretase

ABSTRACT

Compounds of formula (I) are disclosed: wherein R 4  is an alkenyl group of defined structure. The compounds inhibit gamma-secretase, and hence are useful for treatment of Alzheimer&#39;s disease.

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to compounds which modulate the processing of APP byγ-secretase, and hence are useful in the treatment or prevention ofAlzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ), and althoughthe exact role of the plaques in the onset and progress of AD is notfully understood, it is generally accepted that suppressing orattenuating the secretion of Aβ is a likely means of alleviating orpreventing the condition. (See, for example, ID research alert 19961(2):1-7; ID research alert 1997 2(1):1-8; Current Opinion in CPNSInvestigational Drugs 1999 1(3):327-332; and Chemistry in Britain,January 2000, 28-31.)

Aβ is a peptide comprising 39-43 amino acid residues, formed byproteolysis of the much larger amyloid precursor protein. The amyloidprecursor protein (APP or AβPP) has a receptor-like structure with alarge ectodomain, a membrane spanning region and a short cytoplasmictail. Different isoforms of APP result from the alternative splicing ofthree exons in a single gene and have 695, 751 and 770 amino acidsrespectively.

The Aβ domain encompasses parts of both extra-cellular and transmembranedomains of APP, thus its release implies the existence of two distinctproteolytic events to generate its NH₂— and COOH-termini. At least twosecretory mechanisms exist which release APP from the membrane andgenerate the soluble, COOH-truncated forms of APP (APP_(s)). Proteaseswhich release APP and its fragments from the membrane are termed“secretases”. Most APP_(s) is released by a putative α-secretase whichcleaves within the Aβ domain (between residues Lys¹⁶ and Leu¹⁷) torelease α-APP_(s) and precludes the release of intact Aβ. A minorportion of APP_(s) is released by a β-secretase, which cleaves near theNH₂-terminus of Aβ and produces COOH-terminal fragments (CTFs) whichcontain the whole Aβ domain. Finding these fragments in theextracellular compartment suggests that another proteolytic activity(γ-secretase) exists under normal conditions which can generate theCOOH-terminus of Aβ.

It is believed that γ-secretase itself depends for its activity on thepresence of presenilin-1. In a manner that is not fully understoodpresenilin-1 appears to undergo autocleavage.

There are relatively few reports in the literature of compounds withinhibitory activity towards β- or γ-secretase, as measured in cell-basedassays. These are reviewed in the articles referenced above. Many of therelevant compounds are peptides or peptide derivatives.

WO 01/70677 discloses certain sulphonamido-substituted bridgedbicycloalkyl derivatives which are useful in the treatment ofAlzheimer's disease, but neither discloses nor suggests the compounds ofthe present invention.

The present invention provides a novel class of non-peptidic compoundswhich are useful in the treatment or prevention of AD by modulating theprocessing of APP by the putative γ-secretase, thus arresting theproduction of Aβ and preventing the formation of insoluble plaques.

According to the invention there is provided a compound of formula I:

wherein R⁴ is selected from:

X represents H, halogen, CN or methyl;

-   -   R¹ represents H or C₁₋₄alkyl which is optionally substituted        with OH or C₁₋₄alkoxy; or R¹ and R² together complete a        heterocyclic ring of 3-7 members bearing 0-2 substituents, in        addition to R³, selected from halogen, oxo, NO₂, CN, CF₃,        C₁₋₆alkyl, C₂₋₆acyl, C₂₋₆alkenyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl        and Ar;    -   when R¹ represents H or optionally substituted C₁₋₄alkyl, R² and        R³ independently represent H, C₁₋₁₀alkyl, C₃₋₁₀cycloalkyl,        C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, Ar,        heterocyclyl, or heterocyclylC₁₋₆alkyl, wherein the alkyl,        cycloalkyl, alkenyl and alkynyl groups optionally bear one        substituent selected from halogen, CF₃, NO₂, CN, Ar, ArCH₂O,        ArO, —OR¹¹, —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂,        —OCOR¹², —N(R¹¹)₂ and —NR¹¹COR¹²; and the heterocyclic groups        optionally bear up to 3 substituents independently selected from        halogen, NO₂, CN, R¹², Ar, ArCH₂O, ArO, ArOCH₂, —OR¹¹, —SR¹¹,        —SO₂R¹², —COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂ and        —NR¹¹COR¹²;    -   or R² and R³ together with the nitrogen to which they are        mutually attached complete a mono- or bicyclic heterocyclic ring        system of 5-10 ring atoms selected from C, N, O and S, said ring        system optionally having an additional benzene or heteroaryl        ring fused thereto, said heterocyclic system and optional fused        ring bearing 0-3 substituents independently selected from        halogen, oxo, NO₂, CN, R¹², Ar, ArCH₂O, ArO, ArOCH₂, —OR¹¹,        —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂        and —NR¹¹COR¹²;    -   and when R¹ completes a ring with R², R³ represents H,        C₁₋₆alkyl, C₂₋₆acyl, C₂₋₆alkenyl or benzyl;    -   m is 0 or 1, with the proviso that when m is 1 neither R² nor R³        is H and R³ is not acyl, and that m is 1 when X and R¹ are both        H;    -   R¹¹ represents H or R¹²;    -   R¹² represents C₁₋₆alkyl which optionally bears up to 3 halogen        substituents or one substituent selected from CN, OH, C₁₋₄alkoxy        and C₁₋₄alkoxycarbonyl;    -   Y represents halogen, CN or methyl;    -   Z represents OR¹¹ or N(R⁵)R⁶;    -   R⁵ and R⁶ have the same definition as R² and R³ in the        embodiment in which R¹ is H or optionally substituted C¹⁻⁴alkyl;    -   R¹⁴ represents H or C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl or        benzyl, any of which optionally bear up to 3 halogen        substituents or one substituent selected from CN, NO₂, OH,        C₁₋₄alkoxy, CO₂H, C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy,        mino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₂₋₆acylamino,        carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl; and    -   Ar represents phenyl or heteroaryl either of which optionally        bears up to 3 substituents independently selected from halogen,        CF₃, NO₂, CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy;    -   or a pharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroarylC₁₋₆alkyl”, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner. Most suitably, such groups comprise nomore than 4 carbon atoms.

The expression “C₃₋₆cycloalkyl” as used herein refers to nonaromaticmonocyclic or fused bicyclic hydrocarbon ring systems comprising from 3to 10 ring atoms. Bicyclic systems comprising a nonaromatic hydrocarbonring of 3-6 members which is fused to a benzene ring are also included.Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl, decalinyl, tetralinyl and indanyl.

The expression “C₃₋₆ cycloalkyl(C₁₋₆)alkyl” as used herein includescyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

The expression “C₂₋₆acyl” as used herein refers to (C₁₋₅alkyl)carbonylgroups, such as acetyl, propanoyl and butanoyl, including cycloalkylderivatives such as cyclopentanecarbonyl and cyclobutanecarbonyl andhalogenated derivatives such as trifluoroacetyl.

The expression “heterocyclyl” as used herein means a cyclic orpolycyclic system of up to 10 ring atoms selected from C, N, O and S,wherein at least one ring atom is other than carbon and said atom ispart of a non-aromatic ring. Monocyclic systems of up to 6 ring atomsare preferred. Preferably not more than 3 ring atoms are other thancarbon. Suitable heterocyclyl groups include azetidinyl, pyrrolidinyl,terahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, tetrahydropyridinyl, imidazolinyl, dioxanyl,benzodioxanyl and 5-aza-2-oxabicyclo[2.2.1]heptyl. Unless indicatedotherwise, attachment of heterocyclyl groups may be through a carbon ornitrogen atom forming part of the heterocyclic ring. “C-heterocyclyl”indicates bonding through carbon, while “N-heterocyclyl” indicatesbonding through nitrogen.

The expression “heteroaryl” as used herein means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and comprises at leastone ring atom which is other than carbon. Monocyclic systems comprising5 or 6 ring atoms are preferred. Preferably not more than 3 ring atomsare other than carbon. Where a heteroaryl ring comprises two or moreatoms which are not carbon, not more than one of said atoms may be otherthan nitrogen. Examples of heteroaryl groups include pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analoguesthereof. Further examples of suitable heteroaryl ring systems include1,2,4-triazine and 1,3,5-triazine.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may advantageously be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quaternary ammoniumsalts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The compounds of formula I exist as two sets of positional isomers,depending on whether R⁴ is attached at an ortho position relative to thefused ring junction, or at a meta position relative to said junction.Meta attachment is preferred. For each positional isomer, twoenantiomeric forms are possible, depending on which of the two availableortho or two available meta positions is occupied. For each positionalisomer, the invention extends to both enantiomers, as pure compounds oras enantiomeric mixtures in any proportion. Furthermore, structuralformulae depicting one enantiomeric form are to be construed asrepresenting both enantiomeric forms, unless otherwise stated.

The compounds of formula I are alkenyl-substituted benzo-fused bridgedbicycloalkane derivatives comprising a spiro-linked cyclic sulphamidemoiety. The alkenyl group may exist as either of the possiblegeometrical isomers, but the isomer in which X or Y is cis with respectto the benzene ring is preferred.

In the compounds of formula I, R¹⁴ preferably represents optionallysubstituted C₁₋₆alkyl (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, sec-butyl, cyanomethyl, 2-fluoroethyl, methoxyethyl,trifluoromethyl and 2,2,2-trifluoroethyl), C₃₋₇cycloalkyl (such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl),C₃₋₆cycloalkylC₁₋₆alkyl (such as cyclopropylmethyl, cyclobutylmethyl andcyclopentylmethyl), C₂₋₆alkenyl (such as allyl), C₂₋₆alkynyl (such aspropargyl), or optionally substituted phenyl or benzyl. R¹⁴ very aptlyrepresents n-propyl or 2,2,2-trifluoroethyl, an in a particularembodiment R¹⁴ represents 2,2,2-trifluoroethyl.

A subset of the compounds of formula I are in accordance with formulaII:

where X, m, R¹, R² and R³ are as previously defined.

X typically represents H, F, CN or methyl.

R¹ represents H or optionally substituted C₁₋₄alkyl (such ashydroxymethyl), or R¹ together with R² completes a heterocyclic ring asdefined previously. When R¹ and R² complete a ring, X is preferably H.Rings completed by R¹ and R² comprise 3-7 atoms, typically 5 or 6 atoms,and suitable examples include pyrrolidine, piperidine, piperazine,tetrahydropyridine, morpholine, thiomorpholine andthiomorpholine-1,1-dioxide. The ring may bear up to two substituents asdefined previously, in addition to the R³ group. Preferred substituentsinclude halogen, especially fluorine and chlorine, and CF₃. When R¹ andR² complete a ring, R³ represents H, C₁₋₆alkyl (such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl or t-butyl), C₂₋₆acyl (such asacetyl or trifluoroacetyl), C₂₋₆alkenyl (such as allyl), or benzyl. Inthis context, R³ very aptly represents H or benzyl. Specific examples ofrings completed by R¹ and R² include 1-benzylpiperidine and4-trifluoromethylpiperidine.

When R¹ is H or optionally substituted C₁₋₄alkyl, R² and R³independently represent H, C₁₋₁₀alkyl, C₃₋₁₀-cycloalkyl,C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, Ar, heterocyclyl,or heterocyclylC₁₋₆alkyl, wherein the alkyl, cycloalkyl, alkenyl andalkynyl groups optionally bear one substituent selected from halogen,CF₃, NO₂, CN, Ar, ArCH₂O, ArO, —OR¹¹, —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹,—CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂ and —NR¹¹COR¹²; and the heterocyclicgroups optionally bear up to 3 substituents independently selected fromhalogen, NO₂, CN, R¹², Ar, ArCH₂O, ArO, ArOCH₂, —OR¹¹, —SR¹¹, —SO₂R¹²,—COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂ and —NR¹¹COR¹²;

-   -   or R² and R³ together with the nitrogen to which they are        mutually attached complete a mono- or bicyclic heterocyclic ring        system of 5-10 ring atoms selected from C, N, O and S, said ring        system optionally having an additional benzene or heteroaryl        ring fused thereto, said heterocyclic system and optional fused        ring bearing 0-3 substituents independently selected from        halogen, oxo, NO₂, CN, R¹², Ar, ArCH₂O, ArO, ArOCH₂, —OR¹¹,        —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂        and —NR¹¹COR¹²;    -   where Ar, R¹¹ and R¹² are as defined previously.

In this context, R² and R³ typically independently represent H,optionally substituted C₁₋₆alkyl (such as methyl, ethyl, 2-methoxyethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, benzyl, furan-2-ylmethyland pyridin-2-ylmethyl), cycloalkyl (such as cyclopentyl and indanyl),heterocyclyl (such as tetrahydrofuranyl and tetrahydropyranyl) orheterocyclylC₁₋₆alkyl (such as tetrahydropyran-2-ylmethyl,dioxanylmethyl and (4-phenylmorpholin-2-yl)methyl), or R² and R³complete a heterocyclic ring system. Suitable ring systems includepyrrolidine, piperidine, tetrahydropyridine, piperazine, morpholine,thiomorpholine, 2,5-diazabicyclo[2,2,1]heptane,5,6-dihydro-8H-imidazo[1,2-α]pyrazine andspiro[isobenzofuran-1(3H),4′-piperidine]. Preferred ring substituentsinclude halogen, OH, oxo and R¹² groups (such as methyl, ethyl, propyl,hydroxymethyl, methoxymethyl and trifluoromethyl), acetyl,trifluoroacetyl, methoxycarbonyl, phenoxymethyl, pyridyl and phenyl,wherein the pyridyl and phenyl groups optionally bear up to 2substituents selected from halogen (especially chlorine or fluorine),C₁₋₆alkyl and C₁₋₆alkoxy.

When R¹ represents H or optionally substituted C₁₋₄alkyl, examples ofgroups represented by —N(R²)R³ in formula II include N,N-dimethylamino,piperidin-1-yl, morpholin-4-yl, 4-(trifluoroacetyl)piperazin-1-yl,4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl,N-(2-methoxyethyl)-N-methylamino, 4-trifluoromethylpiperidin-1-yl,4,4-difluoropiperidin-1-yl, 5-aza-2-oxabicyclo[2.2.1]hept-5-yl,1,2,3,6-tetrahydropyridin-1-yl, N-furfurylamino, N-(indan-1-yl)amino,N-(pyridin-2-ylmethyl)amino, N,N-bis(2-methoxyethyl)amino,3,3-difluoropyrrolidin-1-yl, 4-hydroxy-4-trifuoromethylpiperidin-1-yl,3-oxopiperazin-1-yl, 3-oxo-4-phenylpiperazin-1-yl,4-methylpiperidin-1-yl, N-(2,2,2-trifluoroethyl)amino,N-(thiophene-2-ylmethyl)amino,N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino,2-phenoxymethylmorpholin-4-yl, 3-(pyridin-3-yl)-pyrrolidin-1-yl,N-(4-phenylmorpholin-2-ylmethyl)amino,N-(tetrahydropyran-2-ylmethyl)amino, N-(tetrahydrofuran-3-yl)amino,3-hydroxypiperidin-1-yl, N-methyl-N-(tetrahydropyran-4-yl)amino,N-(dioxan-2-ylmethyl)amino and N-(tetrahydropyran-4-yl)amino.

In a preferred embodiment, R¹⁴ is 2,2,2-trifluoroethyl, X is F, CN ormethyl, R¹ is H and R² and R³ complete a heterocyclic ring system.

In a particular embodiment, the moiety —N(R²)R³ represents4-trifluoromethylpiperidin-1-yl.

Compounds of formula II in which the moiety —N(R²)R³ represents atertiary amino group (which optionally may form part of a ring) may bein the form of the corresponding N-oxides (i.e. m=1 in formula I or II).When X and R¹ both represent H, the invention is restricted to theaforesaid N-oxides.

Another subset of the compounds of formula I are in accordance withformula III:

where R¹⁴, Y and Z are as previously defined.

Y represents halogen (especially F), CN or methyl.

Z typically represents OH, C₁₋₆alkoxy (especially methoxy or ethoxy) orN(R⁵)R⁶, where R⁵ and R⁶ have the same definition as R² and R³ when R¹is H or optionally substituted C¹⁻⁴alkyl. Thus, Z may represent any ofthe groups listed above as possible embodiments of the moiety —N(R²)R³in formula II.

In a preferred embodiment, R¹⁴ is 2,2,2-trifluoroethyl, Y is F, CN ormethyl, and Z is as previously defined.

In a particular embodiment, Z represents ethoxy.

Specific compounds in accordance with the invention are disclosed in theExamples appended hereto.

The compounds of the present invention have an activity as inhibitors ofγ secretase.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, transdermal patches, auto-injector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums or surfactants such assorbitan monooleate, polyethylene glycol, and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Typical unit dosage forms containfrom 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of theactive ingredient. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The present invention also provides a compound of the invention or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating or preventing Alzheimer'sdisease.

Also disclosed is a method of treatment of a subject suffering from orprone to Alzheimer's disease which comprises administering to thatsubject an effective amount of a compound according to the presentinvention or a pharmaceutically acceptable salt thereof.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, poly(vinylpyrrolidone) or gelatin.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kgper day, and especially about 0.01 to 5 mg/kg of body weight per day.The compounds may be administered on a regimen of 1 to 4 times per day.In some cases, however, dosage outside these limits may be used.

The compounds of formulae II and II may be prepared from the triflatesof formula IV:

where Tf represents trifluoromethanesulphonyl and R¹⁴ has the samemeaning as before.

In one process, the triflate is reacted with carbon monoxide andmethanol to provide the methyl carboxylate V:

where R¹⁴ has the same meaning as before. The reaction takes place inDMSO at 80° C. in the presence of triethylamine,bis(diphenylphosphino)propane and Pd(II) acetate.

Reduction of the ester V to the corresponding benzyl alcohol, followedby oxidation to the corresponding aldehyde, then condensation with(EtO)₂PO—CHX—CO₂Et provides the alkenyl esters VI:

where X and R¹⁴ have the same meanings as before. The reduction may beeffected by treatment with diisobutylaluminium hydride in THF at −78°C., the subsequent oxidation by treatment with pyridinium dichromate indichloromethane, and the condensation takes place in THF at ambienttemperature in the presence of a base such as LiOH.

The compounds of formula VI in which X is other than H correspond tocompounds of formula III in which Z represents ethoxy. Alkalinehydrolysis of these compounds provides the compounds of formula III inwhich Z is OH, which may be coupled with R¹²OH or R⁵R⁶NH where R¹², R⁵and R⁶ have the same meanings as before to provide the remainingcompounds of formula III. Standard techniques of ester- oramide-formation may be used for this purpose.

The alkenyl esters VI may be reduced to the corresponding allyl alcoholsVII(a), which may be reacted with PBr₃ to provide the allyl bromidesVII(b), which in turn undergo nucleophilic displacement with R²R³NH toprovide the amines VII(c):

where X, R¹, R² and R³ have the same meanings as before. The reductionof VI may be effected by treatment with diisobutylaluminium hydride inTHF at −10° C., the subsequent reaction with PBr₃ takes place indichloromethane at −30° C., and the nucleophilic displacement istypically carried out at ambient temperature in dichloromethane in thepresence of a tertiary amine such as diisopropylethylamine.

Alternatively, the aldehydes obtained by sequential reduction andoxidation of esters V may be reacted with acrylonitrile to provideallylic alcohols VA:

where R¹⁴ has the same meaning as before. The reaction takes place inaqueous dioxan in a sealed tube at ambient temperature in the presenceof 1,4-diazabicyclo[2,2,2]octane. Subsequent treatment with PBr₃ andnucleophilic displacement as described above provides an alternativeroute to compounds of formula VII(c) in which X is CN.

The compounds of formula VII(c) correspond to compounds of formula II inwhich R¹ is H and m is 0.

In another process, a triflate IV is reacted with an alkyneHC≡C—CH₂—R^(1a) to provide a compound of formula VIII:

where R^(1a) represents H or C₁₋₄alkyl which is optionally substitutedwith OH or C₁₋₄alkoxy, and R¹⁴ has the same meaning as before. Thereaction takes place in the presence of (Ph₃P)₄Pd(0), Ph₃P, copperiodide and triethylamine in dioxan at 100° C.

Treatment of alkynes VIII with R²R³NH provides the compounds of formulaIX:

where R¹⁴, R^(1a), R² and R³ have the same meanings as before. Thereaction takes place in refluxing dioxan in the presence of (Ph₃P)₄Pd(0)and benzoic acid. The compounds of formula IX correspond to thecompounds of formula II in which X is H, m is 0 and R¹ is C₁₋₄alkylwhich is optionally substituted with OH or C₁₋₄alkoxy.

In another process, a triflate IV is reacted with an alkyneHC≡C—CH₂(CH₂)_(n)NR^(3a) to provide compounds of formula X:

where n is 3 or 4, R^(3a) represents H, C₁₋₆alkyl, C₂₋₆alkenyl or benzyland R¹⁴ has the same meaning as before. The reaction takes place undersimilar conditions to the conversion of IV to VIII.

Cyclisation of the compounds of formula X under similar conditions tothe preparation of compounds IX provides compounds XI:

where n, R¹⁴ and R^(3a) have the same meanings as before. Such compoundscorrespond to compounds of formula II in which X is H, R¹ and R²complete a pyrrolidine or piperidine ring and R³ represents H,C₁₋₆alkyl, C₂₋₆alkenyl or benzyl.

In another process, the triflates IV are converted to boronic acidderivatives XII:

where R represents H or alkyl, or the two OR groups complete a cyclicboronate ester such as the pinacolate. The conversion may be achieved byconventional means using a suitable boron reagent, such asbis(pinacolato)diboron, in the presence of a Pd(II) catalyst such asbis(diphenylphosphinoferrocene)dichloropalladium(II), typically in thepresence of potassium acetate in DMF at 100° C.

Coupling of the boron compounds XII with an iodoalkeneI—CH═CH—CHR¹—N(R²)Boc provides compounds of formula XIII(a):

where R¹ and R² complete a heterocyclic ring, Boc representst-butoxycarbonyl and R¹⁴ has the same meaning as before. The couplingmay be carried out in THF at 60° C. in a sealed tube in the presence oftris(dibenzylideneacetone)dipalladium(0), tributylphosphine and caesiumcarbonate.

Treatment of the compounds XIII(a) with acid provides the deprotectedcompounds XIII(b), which are compounds in accordance with formula II inwhich m is 0, X is H, R¹ and R² complete a ring and R³ is H.

Individual compounds in accordance with formula I may be converted todifferent compounds in accordance with formula I by application of knownsynthetic techniques. Alternatively, such transformations may be carriedout on the precursors of the compounds of formula I. For example,compounds in which the moiety —N(R²)R³ represents a tertiary amino groupmay be converted to the corresponding N-oxides (m=1) by conventionaloxidative techniques, e.g. treatment with m-chloroperoxybenzoic acid atambient temperature in an inert solvent such as dichloromethane.

Where they are not commercially available, the above-mentioned reagentsmay be prepared by conventional routes. The synthesis of triflate IV inwhich R¹⁴ represents 2,2,2-trifluoroethyl is described in the Examples,and analogous routes may be followed for other identities of R¹⁴.

Where more than one isomer can be obtained from the above-describedreaction schemes, then the resulting mixture of isomers can be separatedby conventional means.

Where the above-described processes for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers,these isomers may be separated by conventional techniques such aspreparative chromatography. The novel compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

A typical assay which can be used to determine the level of activity ofcompounds of the present invention is as follows:

-   -   (1) Mouse neuroblastoma neuro 2a cells expressing human app695        are cultured at 50-70% confluency in the presence of sterile 10        mM sodium butyrate.    -   (2) Cells are placed in 96-well plates at 30,000/well/100μL in        minimal essential medium (ME) (phenol red-free)+10% foetal        bovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine,        0.2 mg/ml G418 antibiotic, 10 mM sodium butyrate.    -   (3) Make dilutions of the compound plate. Dilute stock solution        to 5.5% DMSO/110 μM compound. Mix compounds vigorously and store        at 4° C. until use.    -   (4) Add 10 μL compound/well. M plate briefly, and leave for 18 h        in 37° C. incubator.    -   (5) Remove 90 μL of culture supernatant and dilute 1:1 with        ice-cold 25 mM HEPES (pH0.3), 0.1% BSA, 1.0 mM EDTA (+broad        spectrum protease inhibitor cocktail; pre-aliquotted into a        96-well plate). Mix and keep on ice or freeze at −80° C.    -   (6) Add back 100 μL of warm MEM+10% FBS, 50 mM HEPES (pH7.3), 1%        glutamine, 0.2 mg/ml G418, 10 mM sodium butyrate to each well,        and return plate to 37° C. incubator.    -   (7) Prepare reagents necessary to determine amyloid peptide        levels, for example by ELISA assay.    -   (8) To determine if compounds are cytotoxic, cell viability        following compound administration is assessed by the use of        redox dye reduction. A typical example is a combination of redox        dye MTS (Promega) and the electron coupling reagent PES. This        mixture is made up according to the manufacturer's instructions        and left at room temperature.    -   (9) Quantitate amyloid beta 40 and 42 peptides using an        appropriate volume of diluted culture medium by standard ELISA        techniques.    -   (10) Add 15 μL/well MTS/PES solution to the cells; mix and leave        at 37° C.    -   (11) Read plate when the absorbance values are approximately 1.0        (mix briefly before reading to disperse the reduced formazan        product).

Alternative assays are described in Biochemistry, 2000, 39(30),8698-8704.

The Examples of the present invention all had an ED₅₀ of less than 100nM, typically less than 50 nM and in most cases less than 10 nM in atleast one of the above assays.

The following examples illustrate the present invention.

EXAMPLES

Intermediate 1

Step 1

A mixture of2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[α][8]annulen-11-one(15 g; J. Org. Chem 1982, 47, 4329), K₂CO₃ (20.5 g) and benzyl bromide(10.6 ml) in DMF (100 ml) was stirred for 48 hrs at room temperature.The reaction was diluted with water (500 ml) and extracted with EtOAc(3×150 ml). The combined organic phases were washed with water (2×300ml), brine (150 ml), dried and concentrated to give a gummy oil whichcrystallized on standing and after trituration with ether the titlebenzyl ether (19.5 g, 90%) as a white solid (360 MHz ¹H, δ-CDCl₃) 1.32(2H, m), 1.85 (2H, m), 2.57 (2H, m), 2.87 (4H, m), 5.05 (2H, s), 6.82(2H, m), 7.11 (1H, d, J=8.2), 7.37 (5H, m).Step 2

A solution of the product from Step 1 (20 g, 68 mmol), (+/−)tert-butylsulfinamide (9.2 g, 76 mmol) and titanium (IV) ethoxide (tech., 29.2 mL,140 mmol) in dry THF (140 mL) was stirred and heated at reflux undernitrogen for 4 hours. The reaction was allowed to cool to roomtemperature and poured into rapidly stirred brine (160 mL). The mixturewas stirred for 20 minutes, then filtered through Hyflo®, washing withethyl acetate. The filtrate was transferred to a separating funnel. Thelayers were separated, and the aqueous layer was extracted with ethylacetate (×1). The combined organic extracts were washed with brine, thendried (Na₂SO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 20→30% ethyl acetate/hexanes, togive the imine (24.9 g, 93%) as a colourless solid. MS(ES+) 396, MH⁺.Step 3

Sodium hydride (60% dispersion in oil, 3.8 g, 95 mmol) was addedportionwise to a stirred suspension of trimethyl sulfoxonium iodide (21g, 95 mmol) in dry DMSO (150 mL) at room temperature under nitrogen.After 90 minutes at room temperature, a solution of the product fromStep 2 (24.9 g, 95 mmol) in dry DMSO (250 mL) was added such that theinternal temperature remained below 30° C. The mixture was stirred atroom temperature for 4 hours, then quenched with water (1 L). Theprecipitate was collected by filtration. The solid was taken up indichloromethane and washed with brine. The organic layer was dried(Na₂SO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 5→10% ethylacetate/dichloromethane, to give the aziridine (23.2 g, 90%) as acolourless solid. MS(ES+) 410, MH⁺.Step 4

Trifluoroethyl amine (70 mL, 880 mmol) was added to a stirred suspensionof the product from Step 3 (68.4 g, 167 mmol) and anhydrous zinc iodide(54 g, 170 mmol) in dry 1,2-dichloroethane (300 mL) at room temperatureunder nitrogen. The resulting solution was heated at 75° C., protectedfrom light for 24 hours, an additional portion of trifluoroethyl amine(70 mL, 880 mmol) added and the reaction maintained at 75° C. for afurther 16 hours. The reaction was allowed to cool, then diluted withdichloromethane (500 mL) and water (400 mL). Sufficient sodium carbonatewas then added to adjust the aqueous layer to ˜pH 11. The small amountof precipitate was removed by filtration through Hyflo®. The layers wereseparated and the aqueous layer was extracted with dichloromethane (×3).The combined organic extracts were dried (Na₂SO₄), filtered andevaporated. The residue was purified by chromatography on silica,eluting with 5→10% ethyl acetate/dichloromethane, then with 10→20%methanol/dichloromethane, to give the diamine (59.6 g, 88%) as a thickoil. MS(ES+) 405, MH⁺.Step 5

A solution of the product from Step 4 (59.6 g, 147 mmol) and sulfamide(42.5 g, 442 mmol) in dry pyridine (350 mL) was stirred and heated atreflux under nitrogen for 4 hours. The reaction was allowed to cool,then the pyridine was removed in vacuo. The residue was azeotroped withtoluene (×2) and the residue partitioned between dichloromethane (400mL) and 1N hydrochloric acid (400 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (3). The combinedorganic extracts were dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by chromatography on silica, eluting withdichloromethane, then 1→2→4% ethyl acetate/dichloromethane to give thecyclic sulfamide (53 g, 80%) as a colourless solid. ¹H NMR (360 MHz,CDCl₃) δ_(H) 1.34 (2H, m), 1.70 (2H, m), 2.41 (2H, m), 2.62 (2H, m),3.11 (2H, d, J=15.9), 3.20 (1H, d, J=15.9), 3.42 (2H, ABq, J=9.3, 13.3),3.67 (2H, dq, J=2.2, 8.7), 4.76 (1H, s), 5.02 (2H, s), 6.72 (2H, m),6.99 (1H, d, J=7.8), 7.37 (5H, m).Step 6

A solution of the product from Step 5 (3.9 g, 8.4 mmol) inmethanol/ethyl acetate (4:1, 150 mL) was hydrogenated at 35 psi over 10%palladium on carbon (500 mg) for 4 hours at room temperature. Thecatalyst was removed by filtration through Hyfloo. The filtrate wasevaporated, and the residue was purified by filtration through a pad ofsilica, eluting with 50% ethyl acetate/dichloromethane to give thephenol (3.2 g) colourless solid. ¹H NMR(360 MHz, d₆-DMSO) δ_(H) 1.06(2H, m), 1.65 (2H, m), 2.29 (2H, m), 2.42 (2H, m), 3.04 (1H, d, J=15.6),3.11 (1H, d, J=15.6), 3.43 (2H, s), 3.99 (2H, brq, J=9.6), 6.47 (2H, m),6.85 (1H, d, J=8) 7.93 (1H, s), 9.02 (1H, s).Step 7

Pyridine (2.1 mL, 26 mmol) was added dropwise to a stirredsolution/suspension of the product from Step 6 (7.7 g, 20 mmol) andtriflic anhydride (4.3 mL, 25.6 mmol) in dry dichloromethane (200 mL) at0° C. under nitrogen. The cooling bath was removed and the reaction wasstirred at room temperature for 4 hours. Water (300 mL) was added andthe layers were separated. The aqueous layer was extracted withdichloromethane (×2). The combined extracts were washed with brine (×1),then dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby chromatography on silica, eluting with 5% ethylacetate/dichloromethane, to give the triflate (6.7 g, 65%) as an offwhite solid. ¹H NMR (360 MHz, d₆-DMSO) δ_(H) 0.99 (2H, m), 1.71 (2H, m),2.38 (2H, brm), 2.69 (2H, m), 3.16 (1H, d, J=15.7), 3.18 (1H, d,J=15.7), 3.46 (2H, s), 4.02 (2H, brq, J=9.6), 7.18-7.31 (3H, m), 8.04(1H, s).

Example 1

Step 1

A solution of Intermediate 1 (6.7 g, 13 mmol),1,3-bis(diphenylphosphino)propane (540 mg, 1.3 mmol) and triethylamine(25 mL, 180 mmol) in dry DMSO (180 mL) and methanol (120 mL) wasdeoxygenated by bubbling carbon monoxide through the solution for 15minutes. Palladium (II) acetate (300 mg, 1.3 mmol) was added anddeoxygenation was continued for a further 5 minutes. The reaction thenheated at 80° C. for 4 hours, with a slow stream of carbon monoxidebubbling though the solution. The reaction was allowed to cool, thendiluted with water (1 L) and the mixture extracted with ethyl acetate(×3). The combined extracts were washed with brine (×1), then dried(Na₂SO₄), filtered and evaporated. The residue was purified bychromatography on silica, eluting with 100% dichloromethane to 5% ethylacetate/dichloromethane, to give the ester (4.8 g, 88%) as a pale yellowsolid. ¹H NMR (360 MHz, CDCl₃) δ_(H) 1.28 (2H, m), 1.72 (2H, m), 2.48(2H, brm), 2.78 (2H, m), 3.23 (1H, d, J=15.4), 3.27 (1H, d, J=15.4),3.43 (2H, ABq, J=9.5, 11.1), 3.68 (2H, q, J=8.7), 3.90 (3H, s), 4.79(1H, s), 7.17 (1H, d, J=8.3), 7.78 (2H, m).Step 2

Dibal-H (1M in PhMe, 49 mL, 49 mmol) was added slowly to a stirredsolution of the product from Step 1 (5.1 g, 12.2 mmol) in dry THF (100mL) at −78° C. under nitrogen. After 30 minutes the reaction was allowedto warm to −10° C. and maintained at this temperature for 3 hours. Thereaction was quenched with methanol and allowed to warm to roomtemperature. 1N hydrochloric acid (100 mL) was added slowly and themixture extracted with ethyl acetate (×3). The combined extracts werewashed with brine (×1), then dried (Na₂SO₄), filtered and evaporated togive a dark foam (5.2 g) which was used without further purification. ¹HNMR (360 MHz, CDCl₃) δ_(H) 1.35 (2H, m), 1.71 (2H, m), 2.43 (2H, brm),2.68 (1H, d, J=16.1), 2.70 (1H, d, J=16.1), 3.17 (1H, d, J=15.9), 3.20(1H, d, J=15.9), 3.43 (2H, s), 3.69 (2H, q, J=8.7), 4.65 (2H, brs), 4.73(1H, s), 7.10 (3H, m).Step 3

Pyridinium dichromate (6.9 g, 18 mmol) was added to a stirred solutionof the product from Step 2 (5.2 g) in dry dichloromethane (120 mL) atroom temperature. The mixture was stirred at this temperature overnight,then loaded directly on to a pad of silica. The pad was eluted withdichloromethane, then 20% ethyl acetate/dichloromethane to give thealdehyde (4.2 g, 89%) as a pale yellow solid. ¹H NMR (360 MHz, CDCl₃)δ_(H) 1.27 (2H, m), 1.74 (2H, m), 2.50 (2H, brm), 2.82 (2H, m), 3.26(1H, d, J=13.9), 3.30 (1H, d, J=13.9), 3.45 (2H, Abq, J=9.4, 11.5), 3.69(2H, q, J=8.7), 4.79 (2H, s), 7.28 (1H, d, J=7.6), 7.64 (2H, m), 9.96(1H, s).

Step 4

To a solution of aldehyde (0.194 g) from Step 3 and triethyl2-phosphonopropionate (0.357 g) in THF (4 ml) at room temperature wasadded LiOH (36 mg) in one portion and the mixture stirred o/n. Added 1MHCl and extracted with EtOAc (3×), then washed the combined organicextracts with brine, dried and concentrated. The crude product waspurified by chromatography on silica eluting with 15% EtOAc/hexane togive the desired product as a white solid (0.220 g, 93%). ¹H NMR (360MHz, CDCl₃) δ_(H) 1.35 (3H, t, J=7.1), 1.55 (2H, m), 1.73 (2H, m), 2.11(3H, d, J=1.3), 2.46 (2H, m), 2.71 (2H, m), 3.23 (2H, dd, J=16.0, 5.3),3.44 (2H, s), 3.68 (2H, q, J=8.7), 4.26 (2H, q, J=7.1), 4.71 (1H, s),7.12 (952 2H, m), 7.19 (1H, m), 7.62 (1H, m).

Example 2

Triethylamine (0.08 ml) was added to a mixture of the aldehyde fromExample 1, Step 3 (0.150 g), triethyl 2-fluoro-2-phosphonoacetate (0.131g) and magnesium bromide (0.121 g) in THF (20 ml) at 0° C. undernitrogen. The reaction was stirred for 2 hours at 0° C. Added 2N HCl (40ml) and extracted with EtOAc (3×50 ml). The combined organic phases werewashed with brine (50 ml). Drying, concentration and columnchromatography on silica eluting with 20% EtOAc/hexane gave theunsaturated ester (0.121 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 1.27(2H, m), 1.38 (3H, t, J=7.1), 1.72 (2H, m), 2.47 (2H, m), 2.73 (2H, m),3.23 (2H, m), 3.44 (2H, s),3.68 (2H, q, J=8.7), 4.34(2H, q, J=7.1),4.74(1H, s), 6.8 (1H, d, J=35.4), 7.14 (1H, m), 7.40 (2H, m).

Example 3

Prepared by the procedure of Example 1 using triethyl2-fluoro-2-phosphonoacetate instead of triethyl 2-phosphonopropionate.¹H NMR (400 MHz, CDCl₃) δ_(H) 1.27 (3H, t, J=7.1), 1.33 (2H, m), 1.72(2H, m), 2.45 (2H, m), 2.77 (2H, m), 3.20 (2H, dd, J=16.0, 3.4), 3.43(2H, s), 3.68 (2H, q, J=8.7), 4.26 (2H, dq, J=1.6, 7.1), 4.67 (1H, s),6.83 (1H, d, J=23.0), 7.08 (1H, m), 7.27 (2H, m).

Example 4

Step 1.

To a solution of the product (0.204 g) from Example 1 in THF (10 ml) at−10° C. under nitrogen was added 1M DIBAL in toluene (1.73 ml) dropwise.Stirred for 5 hrs, at −10° C. to 0° C., added methanol (few drops) andstirred for 5 mins. Added 1M HCl, allowed to warm to room temperature,extracted with EtOAc (3×) and washed with brine. The combined organicextracts were dried (MgSO₄), filtered and evaporated. The residue waspurified by chromatography on silica gel eluting with 30% EtOAc/hexaneto give the allylic alcohol (0.177 g, 95%).

Step 2.

A solution of the alcohol from Step 1 (60 mg) in dry DCM (3 ml) wascooled to −30° C. Added PBr₃ (0.07 ml, 1.0M in DCM) dropwise and allowedto warm to 0° C. over 1 hr. Added saturated sodium bicarbonate solutionand filtered through celite, washing with DCM. The layers were separatedand the organics dried (MgSO₄), filtered and evaporated. The crudeallylic bromide was dissolved in DCM (2 ml) then4-trifluoromethylpiperidine (85 mg) and DIPEA (90 mg) were added and thereaction was stirred for 16 hours at rt. Added water (10 ml) andextracted with DCM (3×10 ml), the combined organic phases were washedwith brine (20 ml), dried (MgSO₄), filtered and evaporated. The residuewas purified by chromatography on silica gel eluting with 15%EtOAc/hexane then dissolved in Et₂O/MeOH, cooled to 0° C. and bubbled inHCl for 5 mins. Concentrated and triturated with Et₂O to give thedesired compound (HCl salt) as a white powder (55 mg, 65%). ¹H NMR (360MHz, MeOH) δ_(H) 1.19 (2H, m), 1.76 (2H, m), 1.95 (2H, m), 2.06 (3H, s),2.21 (2H, m), 2.45 (2H, m), 2.65 (3H, m), 3.06 (2H, m), 3.31 (2H, m),3.50 (2H, s), 3.68 (2H, m), 3.85 (4H, m), 6.74 (1H, s), 7.13 (3H, m).MS(ES+) 566, MH⁺.

Example 5

Prepared from the product of Example 3 by the method of Example 4. ¹HNMR (360 MHz, MeOH) δ_(H) 1.19 (2H, m), 1.77 (2H, m), 1.86 (2H, m), 2.16(2H, m), 2.46 (2H, m), 2.67 (3H, m), 3.08 (2H, m), 3.31 (2H, m), 3.50(2H, s), 3.64 (2H, m), 3.86 (2H, q, J=9.1), 4.24 (2H, m), 6.88 (1H, d,J=21.4), 7.05 (2H, m), 7.18 (1H, m). MS(ES+) 570, MH⁺.

Example 6

Prepared from the product of Example 2 by the method of Example 4. ¹HNMR (360 MHz, MeOH) δ_(H) 1.18 (2H, m), 1.76 (2H, m), 1.88 (2H, m), 2.22(2H, m), 2.46 (2H, m), 2.64 (3H, m), 3.15 (2H, m), 3.31 (2H, m), 3.50(2H, s), 3.71 (2H, m), 3.86 (2H, q, J=9.1), 4.15 (2H, m), 6.19 (1H, d,J=38.8), 7.14 (1H, m), 7.34 (2H, m). MS(ES+) 570, MH⁺.

Example 7

Step 1

A solution of aldehyde (660 mg, 1.7 mmol) from Example 1, Step 3,acrylonitrile (340 μL, 5.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (190mg, 1.7 mmol) in dioxane/water (1:1, 18 mL) was stirred at roomtemperature under nitrogen in a sealed tube for 10 days. The dioxane wasremoved in vacuo and the aqueous layer was extracted withdichloromethane (×4). The combined extracts were dried (Na₂SO₄),filtered and evaporated. The residue was purified by chromatography onsilica, eluting with 5→10→20% ethyl acetate/dichloromethane, to give thealcohol (674 mg, 90%) as a colourless foam: ¹H NMR (400 MHz, CDCl₃)δ_(H) 1.67-1.72 (2H, m), 2.42-2.45 (2H, m), 2.69 (2H, dd, J=16.0, 7.7),3.15-3.21 (2H, m), 3.42 (2H, s), 3.68 (2H, q, J=8.7), 4.88 (1H, br s),5.27 (1H, s), 6.05 (1H, m), 6.13-6.15 (1H, m), 7.11-7.16 (3H, m).

Step 2

Phosphorus tribromide (1.0 M in dichloromethane, 115 μL, 0.115 mmol) wasadded to a solution of the alcohol from Step 1 (100 mg, 0.23 mmol) indry dichloromethane (2 mL) at 0° C. under nitrogen. The reaction wasstirred at 0° C. for 30 minutes, then at room temperature for 1 hour.The reaction was recooled in an ice bath, then quenched with saturatedaqueous sodium hydrogen carbonate (2 mL). The mixture was partitionedbetween dichloromethane and water, the layers separated and the aqueouslayer extracted with dichloromethane (×2). The combined extracts werewashed with brine (×1), dried (Na₂SO₄), filtered and evaporated to givethe allylic bromide. This was used without further purification.

The bromide was taken up in dry dichloromethane (1 mL) at roomtemperature under nitrogen. Diisopropylethylamine (200 μL, 1.15 mmol)and 4-trifluoromethylpiperidine (150 mg, 1.0 mmol) were added. Thesolution was stirred at room temperature overnight, then partitionedbetween dichloromethane and saturated aqueous sodium hydrogen carbonate.The aqueous layer was extracted with dichloromethane (×2), and thecombined extracts washed with brine (×1), dried (Na₂SO₄), filtered andevaporated. The residue was purified by chromatography on silica,eluting with 2→4→6→8% ethyl acetate/dichloromethane, to give the amine(55 mg, 41%) as a colourless solid: ¹H NMR (360 MHz, CDCl₃) δ_(H)1.29-1.34 (2H, m), 1.67-1.76 (4H, m), 1.84-1.88 (2H, m), 1.98-2.12 (3H,m), 2.22-2.50 (2H, m), 2.74 (2H, dd, J=16.1, 7.7), 3.01-3.06 (2H, m),3.20-3.27 (4H, m), 3.43 (2H, s), 3.68 (2H, q, J=8.7), 4.69 (1H, s), 7.02(1H, s), 7.16 (1H, d, J=7.9), 7.49 (1H, s), 7.59 (1H, d, J=7.9). MS(ES+)577, MH⁺.

Example 8

Step 1

Prepared by the procedure of Example 1 Step 4 by condensation of thealdehyde of Example 1 Step 3 with methyl diethyl phosphonoacetate. ¹HNMR (360 MHz, CDCl₃) δ_(H) 1.30 (2H, m), 1.73 (2H, m), 2.46 (2H, brm),2.72 (2H, m), 3.23 (2H, d, J=15.9), 3.44 (2H, s), 3.68 (2H, q, J=8.7),3.80 (3H, s), 4.65 (2H, brs), 4.80 (1H, s), 6.40 (1H, d, J=16), 7.11(1H, d, J=7.7), 7.27 (2H, m), 7.66 (1H, d, J=16).Step 2

Prepared from the product of Step 1 using the procedure of Example 4.The enantiomers were separated by chiral hplc (chiralcel OD, 25% (25 MMIBU—NH₂ in MEOH)/CO₂ 100 bar, 35° C.). The first eluted enantiomer wasdissolved in Et₂O/MeOH, cooled to 0° C. and bubbled in HCl for 5 mins.Concentrated and triturated with Et₂O to give the desired compound. ¹HNMR (400 MHz, DMSO) δ_(H) 1.09 (2H, m), 1.45 (2H, dq, J=3.6, 12.4), 1.68(2H, m), 1.77 (2H, m), 1.95 (2H, m), 2.26 (1H, m), 2.35 (2H, m), 2.56(2H, m), 2.95 (2H, m), 3.15 (4H, m), 3.45 (2H, s), 4.01 (2H, q, J=9.6),6.22 (1H, dt, J=15.9, 6.6), 6.45 (1H, d, J=15.9), 7.04 (1H, m), 7.16(2H, m), 7.99 (1H, s). MS(ES+) 552, MH⁺.

Step 3

A mixture of the allylic amine from Step 2 (21 mg) and mCPBA (9 mg) inDCM (2 ml) was stirred at rt for 20 minutes. Saturated sodiumbicarbonate solution was added and the reaction was extracted with DCM(×3). The combined organic extracts were dried (MgSO₄), filtered andevaporated. The residue was purified by chromatography on silica geleluting with 5% MeOH/DCM to give the title compound (10 mg, 45%). ¹H NMR(360 MHz, MeOH) δ_(H) 1.19 (2H, m), 1.74 (2H, m), 1.86 (2H, m),2.28-2.44 (6H, m), 2.64 (2H, m), 3.31 (5H, m), 3.49 (2H, s), 3.85 (2H,q, J=9.2), 4.04 (2H, d, J=7.4), 6.49 (1H, dt, J=15.7, 7.4), 6.79 (1H, d,J=15.7), 7.08 (1H, d, J=7.6), 7.24 (2H, m). MS(ES+) 568, MH⁺.

Example 9

Step 1

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.3 g, 17.4 mmol) wasadded to a mixture of 6-heptynoic acid (1.1 g, 8.7 mmol), benzylamine(950 μl, 8.7 mmol), 1-hydroxybenzotriazole (1.2 g, 8.7 mmol) andtriethylamine (2.4 ml, 17.4 mmol) in tetrahydrofuran (25 ml) and themixture was stirred at room temperature for 16 hours. The reaction wasdiluted with sodium hydrogen carbonate (sat, 60 ml) and extracted withethyl acetate (2×100 ml). The extracts were washed with brine, dried(MgSO₄) and evaporated in vacuo to a brown solid (2.1 g, 99%). (ES+) 216([MH]⁺).Step 2

Lithium aluminium hydride (1 m in THF, 10 ml, 10 mmol) was added to asolution of the amide (Step 1) (1.0 g, 4.6 mmol) in THF (20 ml) and themixture was heated at reflux for 16 hours. The reaction was cooled inice and treated successively with water (0.4 ml), sodium hydroxide (0.4ml) and water (1.2 ml) allowing 10 minutes between additions. Themixture was filtered through a bed of celite® and washed through withTHF. The filtrate was evaporated in vacuo to a yellow oil (924 mg, 99%).(ES+) 202 ([MH]⁺).Step 3

A mixture of Intermediate 1 (300 mg, 0.6 mmol), alkyne from Step 2 (482mg, 2.4 mmol), tetrakis-triphenylphospine palladium(0) (35 mg, 5 mol %),triphenylphosphine (16 mg, 10 mol %) and copper iodide (12 mg, 10 mol %)in triethylamine (5 ml) in a sealed tube, was purged with nitrogen andthen heated at 90° C. for 16 hours. The reaction was diluted with sodiumhydrogen carbonate (sat, 30 ml) and extracted with ethyl acetate (2×20ml). The extracts were washed with water (×3) and brine, dried (MgSO₄)and evaporated in vacuo to a dark oil, which was purified by flashcolumn chromatography on silica eluting with DCM:MeOH:NH₃(aq) (120:8:1)to give a brown gum. The gum was further purified flash columnchromatography on silica eluting with EtOAc in isohexane (50%+1%NH₃(aq)) to give the desired compound as a clear foam (241 mg, 72%). δ(¹H, 400 MHz, CDCl₃) 1.28-1.32 (2H, m), 1.45-1.71(8H, m), 2.38-2.44 (4H,m), 2.60-2.70 (4H, m), 3.16 (2H, dd, J=16.0 & 10.1 Hz), 3.42 (2H, s),3.67 (2H, q, J=8.6 Hz), 3.79 (2H, s), 7.00 (1 H, d, J=7.8 Hz), 7.13-7.16(2H, m), and 7.22-7.32 (4 H, m). (ES+) 560 ([MH]⁺).

Step 4

A solution of the alkyne from Step 3 (115 mg, 0.21 mmol), benzoic acid(1.0 M in dioxane, 20 μl, 0.02 mmol) and tetrakis-triphenylphospinepalladium(0) (13 mg, 0.01 mmol) in dioxane (4.0 ml) was degassed andheated at reflux for 48hours. The reaction was purified by SCX ionexchange resin eluting with ammonia (2M in methanol) to give afterevaporation a dark gum. The gum was further purified by flash columnchromatography on silica eluting with EtOAc:isohexane (1:1) to give apale yellow foam (41 mg, 36%). δ (¹H, 400 MHz, CDCl₃) 1.25-1.48 (3H, m),1.48-1.76 (7H, m), 1.88-2.08 (1H, m), 2.42-2.44 (2H, m), 2.67 (2H, dd,J=16.0 & 7.7 Hz), 2.80-2.87 (2H, m), 3.10 (2H, dd, J=13.5 & 4.7 Hz),3.17 (2H, dd, J=16.0 & 7.0 Hz), 3.42 (2H, s), 3.64-3.70 (2H, m), 4.08(1H, d, J=13.6 Hz), 4.66 (1H, Brs), 6.20-6.27 (1H, m), 6.47 (1H, d,J=16.0 Hz), 7.00 (1 H, d, J=8.8 Hz),7.04 (1H, s), 7.07-7.15 (1H, m),7.19-7.23 (1H, s) and 7.28-7.33 (4H, m). (ES+) 560 ([MH]⁺).

Example 10

Step1

A mixture of Intermediate 1 (100 mg, 0.2 mmol), 3-butyn-1-ol (61 μl, 0.8mmol), tetrakis-triphenylphospine palladium(0) (12 mg, 5 mol %),triphenylphosphine (5.2 mg, 10 mol %) and copper iodide (4 mg, 10 mol %)in triethylamine (3 ml) was purged with nitrogen and then heated at 100°C. for 16 hours. Dioxane (3 ml), tetrakis-triphenylphospine palladium(0)(12 mg, 5 mol %), triphenyl phosphine (5.2 mg, 10 mol %) and copperiodide (4 mg, 10 mol %) were added and the reaction was heated at 100°C. for 48 hours. The reaction was diluted with sodium hydrogen carbonate(sat, 20 ml) and extracted with ethyl acetate (2×25 ml). The extractswere washed with water (×3) and brine, dried (MgSO₄) and evaporated invacuo to a brown gum, which was purified by flash column chromatographyon silica eluting with EtOAc:isohexane (2:3) to give a white solid (30mg, 35%). δ (¹H, 400 MHz, CDCl₃) 1.25-1.34 (2H, m), 1.68-1.72 (2H, m),1.77 (1H, t, J=6.2 Hz), 2.43 (2H, t, J=7.2 Hz), 2.61-2.71(4H, m), 3.17(2H, dd, J=16.0 & 7.4 Hz), 3.42 (2H, s), 3.67 (2H, q, J=8.7 Hz), 3.81(2H, q, J=6.2 Hz), 4.66 (1H, brs), 7.02 (1 H, d, J=8.2 Hz), and7.17-7.18 (2H, m).

Step 2

A solution of the product of Step 1 (24 mg, 0.06 mmol),4-trifluoromethyl piperidine (9 mg, 0.05 mmol), benzoic acid (0.1M indioxane, 60 μl, 0.0066 mmol) and tetrakis-triphenylphospine palladium(0)(4 mg, 5 mol %) in dioxane (0.4 ml) was degassed and heated at refluxfor 65 hours. The reaction was purified by SCX ion exchange resineluting with ammonia (2M in methanol) to give after evaporation a palegum. The gum was further purified by preparative TLC eluting with ethylacetate to give a pale gum (5 mg, 15%). (¹H, 360 MHz, CDCl₃) 1.25-1.41(2H, m), 1.53-2.04 (7H, m), 2.13-2.19 (2H, m), 2.44-2.55 (3H, m),2.65-2.72 (3H, m) 2.87-2.91 (1H, m), 3.05 (1H, d, J=11.2 Hz), 3.16-3.32(3H, m), 3.43 (2H, s), 3.55-3.71 (4H, m), 4.72 (1H, brs), 6.08 (1H, dd,J=16.0 & 8.9 Hz), 6.48 (1H, d, J=16.0 Hz) and 7.04-7.15 (3 H, m). (ES+)582 ([MH]⁺).

Example 11

Step 1.

A solution of Intermediate 1 (0.508 g), bis (pinacolato)diboron (0.279g), Pd(dppf)Cl₂.DCM (82 mg), dppf (55 mg) and potassium acetate (0.294g) in dry degassed DMF (7 ml) was heated at 100° C. under nitrogen for 3hours. The reaction was allowed to cool and poured into water (35 ml)and extracted with EtOAc (3×20 ml). The combined organic phases werewashed with water (30 ml) then brine (50 ml). Drying, concentration andcolumn chromatography on silica eluting with 15-20% EtOAc/hexane gavethe boronate ester (0.375 g, 77%).

Step 2.

Triethylamine (8.0 ml), 4-trifluoromethylpiperidine (8.00 g) and BOC₂O(12.5 g) in THF (100 ml) was stirred for 16 hours at rt. Added water (60ml) and extracted with EtOAc (3×50 ml). The combined organic phases werewashed with brine (50 ml). Drying, concentration and columnchromatography on silica eluting with 5% EtOAc/hexane gave theBOC-protected amine (12.51 g, 95%).

Step 3.

Sec-butyllithium (7 ml, 1.3M in cyclohexane) was added to a solution ofthe product from Step 2 (2.00 g) and TMEDA (1.2 ml) in dry ether (15 mL)at −78° C. under nitrogen. The reaction was stirred at −20° C. for 30mins then cooled to −78° C. Dimethylformamide (0.9 ml) in dry ether (2ml) was added and the reaction was stirred at −78° C. for 45 mins. Thereaction was quenched with saturated ammonium chloride solution (20 ml)and extracted with EtOAc (3×20 ml). The combined organic phases werewashed with brine (20 ml). Drying, concentration and columnchromatography on silica eluting with 10% EtOAc/hexane gave the 2-formylderivative of the BOC-protected amine (2.083 g, 94%).

Step 4.

A solution of the aldehyde from Step 3 (0.337 g) and iodoform (0.943 g)in dry THF (10 ml) was added dropwise to chromium II chloride (0.884 g)in dry THF (10 ml). The reaction was stirred in the dark for 16 hours atrt then saturated ammonium chloride solution (20 ml) was added. Themixture was extracted with EtOAc (3×30 ml). The combined organic phaseswere washed with water (20 ml). Drying, concentration and columnchromatography on silica eluting with 5% ether/hexane gave the2-(2-iodoethenyl) derivative of the BOC-protected amine (0.126 g, 26%).

Step 5.

A solution of the boronate from Step 1 (0.166 g), the vinyl iodide fromStep 4 (0.126 g), Pd₂dba₃ (7 mg), tributylphosphine (93 μl, 0.2M indioxan) and cesium carbonate (0.304 g) in degassed aqueous THF (3 ml)was heated at 60° C. in a sealed tube for 16 hours. The reaction wasallowed to cool, added water (10 ml) and extracted with EtOAc (3×10 ml).The combined organic phases were washed with brine (20 ml). Drying,concentration and column chromatography on silica eluting with 10-20%EtOAc/hexane gave the Boc-protected product (0.150 g, 75%). The productwas dissolved in Et₂O, cooled to 0° C. and bubbled in HCl for 5 mins.Concentration and trituration with Et₂O gave the title compound as theHCl salt. ¹H NMR (360 MHz, MeOH) δ_(H) 1.19 (2H, m), 1.75 (2H, m), 1.93(1H, m), 2.17 (3H, m), 2.45 (2H, m), 2.65 (2H, m), 2.95 (1H, m), 3.31(5H, m), 3.49 (2H, s), 3.86 (2H, q, J=9.2), 4.36 (2H, m), 6.43 (1H, dd,J=15.6, 7.9), 6.85 (1H, d, J=15.6), 7.11 (1H, d, J=7.9), 7.27 (2H, m).MS(ES+) 538, MH⁺.

1. A compound of formula I:

wherein R⁴ is selected from:

X represents H, halogen, CN or methyl; R¹ represents H or C₁₋₄alkylwhich is optionally substituted with OH or C₁₋₄alkoxy; or R¹ and R²together complete a heterocyclic ring of 3-7 members bearing 0-2substituents, in addition to R³, selected from halogen, oxo, NO₂, CN,CF₃, C₁₋₆alkyl, C₂₋₆acyl, C₂₋₆alkenyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyland Ar; when R¹ represents H or optionally substituted C₁₋₄alkyl, R² andR³ independently represent H, C₁₋₁₀alkyl, C₃₋₁₀cycloalkyl,C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, Ar, heterocyclyl,or heterocyclylC₁₋₆alkyl, wherein the alkyl, cycloalkyl, alkenyl andalkynyl groups optionally bear one substituent selected from halogen,CF₃, NO₂, CN, Ar, ArCH₂O, ArO, —OR¹¹, —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹,—CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂ and —NR¹¹COR¹²; and the optionally bear upto 3 substituents independently selected from halogen, NO₂, CN, R¹², Ar,ArCH₂O, ArO, ArOCH₂, —OR¹¹, —SR¹¹, —SO₂R¹², —COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂,—OCOR¹², —N(R¹¹)₂ and —NR¹¹COR¹²; or R² and R³ together with thenitrogen to which they are mutually attached complete a mono- orbicyclic heterocyclic ring system of 5-10 ring atoms selected from C, N,O and S, said ring system optionally having an additional benzene orheteroaryl ring fused thereto, said heterocyclic system and optionalfused ring bearing 0-3 substituents independently selected from halogen,oxo, NO₂, CN, R¹², Ar, ArCH₂O, ArO, ArOCH₂, —OR¹¹, —SR¹¹, —SO₂R¹²,—COR¹¹, —CO₂R¹¹, —CON(R¹¹)₂, —OCOR¹², —N(R¹¹)₂ and -NR¹¹COR¹²; and whenR¹ completes a ring with R², R³ represents H, C₁₋₆alkyl, C₂₋₆acyl,C₂₋₆alkenyl or benzyl; m is 0 or 1, with the proviso that when m is 1neither R² nor R³ is H and R³ is not acyl, and that m is 1 when X and R¹are both H; R¹¹ represents H or R¹²; R¹² represents C₁₋₆alkyl whichoptionally bears up to 3 halogen substituents or one substituentselected from CN, OH, C₁₋₄alkoxy and C₁₋₄alkoxycarbonyl; Y representshalogen, CN or methyl; Z represents OR¹¹ or N(R⁵)R⁶; R⁵ and R⁶ have thesame definition as R² and R³ in the embodiment in which R¹ is H oroptionally substituted C₁₋₄alkyl; R¹⁴ represents H or C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,phenyl or benzyl, any of which optionally bear up to 3 halogensubstituents or one substituent selected from CN, NO₂, OH, C₁₋₄alkoxy,CO₂H, C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, C₂₋₆acylamino, carbamoyl, C₁₋₄alkylcarbamoyl anddi(C₁₋₄alkyl)carbamoyl; and Ar represents phenyl or heteroaryl either ofwhich optionally bears up to 3 substituents independently selected fromhalogen, CF₃, NO₂, CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 of formula II:

or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 2 wherein R¹ and R² complete a heterocyclic ring of 5 or 6atoms and R³ represents H, C₁₋₆alkyl, C₂₋₆acyl or benzyl.
 4. A compoundaccording to claim 2 wherein R¹ is H or optionally substituted C₁₋₄alkyland R² and R³ complete a heterocyclic ring system.
 5. A compoundaccording to claim 4 wherein R¹⁴ is 2,2,2-trifluoroethyl, X is F, CN ormethyl, and R¹ is H.
 6. A compound according to claim 4 wherein m is 1and X and R¹ are both H.
 7. A compound according to claim 1 of formulaIII:

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 7 wherein Y represents F, CN or methyl and Z represents OH,C₁₋₆alkoxy or N(R⁵)R⁶.
 9. A compound according to claim 8 wherein R¹⁴represents 2,2,2-trifluoroethyl and Z represents ethoxy.
 10. Apharmaceutical composition comprising a compound according to anyprevious claim 1 and a pharmaceutical carrier. 11-12. (canceled)
 13. Amethod of treatment of a subject suffering from or prone to Alzheimer'sdisease comprising administering to that subject an effective amount ofa compound according to claim 1.